Hypertension (HTN) is associated with deficient cerebral vascular regulation, impaired vasoreactivity (VR) and perfusion. These deficits lead to hypoperfusion, brain damage and cognitive impairment. White matter lesions (WML), resulting from HTN, contribute to the impairment in cerebral blood flow (CBF) and autoregulation. Deficient autoregulation makes CBF more dependent on perfusion pressure (mean arterial pressure: MAP). Consequently, in subjects with HTN (and even more so with HTN and WML) the relationship between MAP and CBF may be stronger than in healthy individuals. Verifying this hypothesis has important implications, as it may help to optimally target blood pressure (BP) for adequate perfusion in subjects with HTN: Should stronger dependence of CBF on MAP be established excessive reduction of blood pressure may prove detrimental. Both too high and too low BP is likely harmful. We plan to provide evidence for an optimum. The study will include 180 cognitively normal hypertensive elderly (90 without WML (HTN/WML-), 90 with WML (HTN/WML+)) and 50 normotensive controls (NL), examined at baseline, 12 and 24 months later. We propose to test the following four hypotheses: 1. CBF. a. At cross-section the MAP-CBF relationships are increasingly stronger across 3 groups (NL, HTN/WML-, HTN/WML+), reflecting progressive dysfunction of autoregulation. b. Longitudinally: baseline BP predicts CBF preservation at follow-up. 2. VR. a. At cross-section, VR decreases across 3 groups, reflecting increasingly impaired vascular function. b. Longitudinally: baseline BP metrics predict VR preservation at follow-up. 3. Cognition. a. At cross-section, the relationship between cognition and BP, CBF, and VR is progressively stronger across 3 groups. b. Longitudinally: baseline BP, CBF and VR predict change in cognition at follow-up. 4. Brain measures. a. Longitudinally, baseline BP, CBF and VR predict preservation of brain volumes and brain tissue metabolic integrity at follow- up. We propose to determine in each group: 1) baseline BP values optimal for CBF and VR preservation at follow-up, and 2) baseline BP, CBF and VR values optimal for cognition and brain preservation at follow-up. We will test whether effects of BP on cognition and the brain are mediated through CBF and VR. CBF and VR will be measured with non- invasive, susceptibility-artifact resistant arterial spin labeling MRI using a carbon dioxide rebreathing challenge. Brain perfusion and volume will be evaluated globally and locally to determine regional vulnerability. Magnetic resonance spectroscopy will be used to assess brain metabolic integrity based on global N-acetylaspartate. These data will likely improve our understanding of the relationships between BP, brain perfusion and cognition in HTN. Documenting that HTN/WML- and HTN/WML+ groups have different optimum BP for preservation of perfusion, cognition and brain measures will confirm the need to individually optimize HTN treatment. Advanced imaging techniques will help to inform us as to the target BP values. PUBLIC HEALTH RELEVANCE: Hypertension (HTN) is associated with impaired cerebral vasoreactivity (VR) and flow autoregulation, which may result in greater dependence of cerebral blood flow (CBF) on perfusion pressure. Verifying this hypothesis has important implications for targeting blood pressure (BP) to ensure adequate perfusion in subjects with HTN: Should it be demonstrated, excessive BP reduction may prove detrimental for brain and cognition. Using novel MRI techniques we will systematically examine relationships between BP, CBF, VR, brain measures and cognitive performance in different groups of hypertensive subjects. We plan to provide an evidence for an optimum BP that maximizes the probability of brain and cognition preservation.